Outline

Purpose: New treatment modalities exploit the reduction of co-irradiated normal-tissue volume to allow an increase of tumor dose. Application of e.g. proton therapy thus requires the extrapolation of photon-based clinical experience using predictive models of e.g. normal tissue damage. Recently, we tested the applicability of the Critical-Volume (CV) model to estimate lung complication risks. Classically, in the CV model a local-dose-based tissue damage model (TDM) is used to calculate the risk of local tissue damage, which is subsequently translated into the risk of loss of organ function. However, in the lung also out-of-field damage has been observed. The aim of the current work is to develop a more accurate, histology-based tissue-damage model.

Methods: Rats were irradiated with graded doses to various sub-volumes of the lung using 150 MeV plateau protons. 8 weeks post-irradiation lung-tissue samples were collected inside and outside the irradiated region. TDMs were tested by fitting to several types of histological changes. Subsequently, consistency between the conventional TDM and histology data is tested. Next, the data were used to develop and test a new TDM. Finally, consistency between the modified CV model containing the new TDM, and published lung function [1] data was tested.

Results: Out-of-field damage and irradiated-volume dependent in-field damage was observed. This could not be described by the conventional local-dose based TDM. A novel TDM was formulated, assuming that local tissue damage occurs if one or both of two basic forms of local damage occur: 1) local-dose dependent direct damage and 2) indirect damage depending on the entire lung-dose distribution. This TDM describes all types of local tissue damage observed. The CV model, enhanced with the new TDM, described the published [1] function data.

Conclusion: Based on observed tissue damage in the lung, a novel local tissue-damage model was developed. Using this model, local tissue damage and the consequential risk of loss of lung function could be described in a single modeling framework. Because it is based on actually observed tissue damage and validated in data on organ function loss, it is expected to be more accurate than empirical concepts. For application in patients, the model needs to be fitted to clinical data first. The resulting model may allow a better extrapolation from photon-based data and lead to a more optimal implementation of proton therapy.